Role of Draxin in Forebrain Connectivity and Complex Behaviors

描述（由申请人提供）：胼胝体（CC）是连接大脑半球的主要纤维束，用于协调大脑半球之间的信息传递。在神经发育和神经精神障碍中观察到该结构的畸形，包括自闭症、精神分裂症、注意缺陷多动障碍、双相情感障碍和抽动秽语综合征，其发生率高于一般人群。由于所有这些疾病主要通过行为标准进行诊断，因此了解CC是否在与这些标准相关的行为中发挥作用是很重要的。连合的发育和功能研究需要易处理的动物模型。我们已经确定了化学排斥轴突导向基因Draxin的编码区中的突变，该突变似乎是BTBR T+ Itpr 3 tf/J（BTBR）小鼠中所见连合表型的原因。由于BTBR还显示出与自闭症的关键特征相关的几种行为缺陷，因此它提供了一个极好的机会来评估Draxin突变在CC形成和自闭症相关行为中的作用。我们的长期目标是阐明前脑连接缺陷的遗传基础以及这些缺陷对神经发育和神经精神相关行为的影响。这个R21项目的目标是确定Draxin在CC发展和自闭症相关行为中的作用。本研究的目的是：1）阐明Draxin在不同遗传背景下连合发育中的作用; 2）确定Draxin依赖性连合畸形在行为表现中的重要性。我们假设Draxin突变将导致结构和行为缺陷，并预测CC大小与行为表现相关，并且它可以作为复杂疾病的标志物。这项研究应该导致更好地了解CC发展的生物学基础以及随后对自闭症和其他复杂疾病的社会，运动和认知方面的影响。

DESCRIPTION (provided by applicant): The corpus callosum (CC) is the main fiber tract connecting the cerebral hemispheres and serves to coordinate the transfer of information between them. Malformations in this structure have been observed in neurodevelopmental and neuropsychiatric disorders including autism, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder and Tourette syndrome more frequently than in the general population. As all of these disorders are diagnosed primarily by behavioral criteria, it is importat to know if the CC plays a role in behaviors relevant to these criteria. Commissure development and function studies require tractable animal models. We have identified a mutation in the coding region of the chemorepulsive axon guidance gene Draxin that appears to be responsible for the commissural phenotype seen in BTBR T+ Itpr3tf/J (BTBR) mice. As BTBR also displays several behavioral deficits relevant to the key characteristics of autism, it affords an excellent opportunity to evaluate the role of Draxin mutation in CC formation and autism-relevant behaviors. Our long-term goal is to elucidate the genetic basis of deficits in forebrain connectivity and the impact of these deficits on neurodevelopmental and neuropsychiatric related behaviors. The goal of this R21 project is to determine the role of Draxin in CC development and autism relevant behaviors. The objectives of this research project are: 1) to elucidate the role of Draxin in commissural development in different genetic backgrounds and 2) to determine the importance of Draxin-dependent commissure malformation in behavioral performance. We hypothesize that Draxin mutations will cause both structural and behavioral deficits and predict that CC size is associated with behavioral performance and that it may serve as a marker for complex disorders. This research should lead to a better understanding of the biology underlying CC development and the subsequent effects on the social, motor and cognitive aspects of autism and other complex disorders.